Saturday, April 11, 2009

What happens in untreated type 1 diabetes?

Type 1 diabetes is characterized by autoimmune destruction of beta cells in the islets of Langerhans, which results in lack of insulin secretion (1). Glucose, then cannot be taken up by cells leading to hyperglycemia and osmotic diuresis (1). The low insulin will also stimulate hepatic glycogenolysis and gluconeogenesis to produce glucose released into blood leading into accentuated hyperglycemia (1).

What’s more is that gluconeogenesis becomes chronic depleting body proteins to break down into amino acids (1). Muscle,in effect, atrophes converting to glucose and lost through the diuresis (1). Weakness, fatigue and weight loss all occur (1).

One example of proteosomal degradation relies on activation of ubiquitin, steps of which are inhibited by insulin (2p208). Insulin also antagonizes activation of a few enzymes—such as the phosphorylation of phenylalanine hydroxylase—responsible for amino acid oxidation (2). The catabolism of amino acids involve transamination or damination (2p209). The amino groups are form alpha-ketobutyrate and ammonia, which must be removed in the urea cycle (2p209).

A mixture of amino acids that is high in alanine and glutamine would be released into the blood (2p246). Alanine, in particular, is a preferred substrate for gluconeogenesis and also stimulates secretion of glucagon, which stimulates gluconeogenesis (2p246).

Deamination/transamination of glycine, serine, cysteine, tryptophan and threonine leaves skeletons oxaloacetate and pyruvate ready for glucose production (2p212). Apart from those, phenylalanine and tyrosine could also be used for glucose when degraded to fumarate (2p212). Valine and methionine are gluconeogenic and isoleucine and threonine are partially glucogenic and partially ketogenic (2p212). Leucine and lycine would not contribute to gluconeogenesis since theyare ketogenic and catabolized to acetyl CoA (2p212).

Because muscle protein provides most of amino acids, particularly in stress situations, muscle cachexia occurs (2p242). The degradation of fast-twitch muscle would be more pronounced than that of the red slow-twitch (2p242). The protein degradation would not be unlike that of starvation with each gram of nitrogen equivalent to 30g of hydrated lean tissue (2p246).

Ketoacidosis is also a logical result. Just as in fasting and starvation, lack of insulin in type 1 diabetes disabling uptake of glucose in cells would lead tissues to use fatty acid oxidation for energy (apart from amino acids) (2p247). Fatty acid oxidation provides energy through production of acetyl CoA, a TCA cycle substrate (2p160). The acetyl CoA use can end up in the "overflow" pathway of ketone body formation (2p160). The ketones would be used as a source of fuel, but in excess can disturb acid-base balance causing acidosis (2p160;2p247).